1. Field of the Invention
The present invention relates to a menthol derivative represented by the following Formula 1 and a method for preparing the menthol derivative. More particularly, the present invention relates to a menthol derivative wherein menthol and 3-aminopropylphosphoric acid form a phospho-diester bond, and therefore, it can be decomposed by the enzyme to exhibit both the activities of menthol and 3-aminopropylphosphoric acid in the living body. 
2. Description of the Related Arts
Menthol is known as a main component of peppermint, and the peppermint is a well-known fragrant plant. According to oriental medicine, the peppermint has effects of clearing and suppressing cold, and, because it has heat dispelling and perspiration effects, it has been used for itching, pains such as arthritis and neuralgia, tuberculosis and gastroenteric disorder, etc. Further, because it shows the effects on central blood vessel and relaxation of blood vessel, it has been used for paralysis. And, peppermint tea is known as good for stress and nervousness.
These effects of the peppermint seem to originate from L-menthol, the main component of peppermint. L-menthol is expressed chemically as C15H20O and transparent needle-shaped crystal with fresh fragrance. It is not dissolved in aqueous phase (water), but well dissolved in ethanol, ether and chloroform. The menthol having these features is obtained from extraction of peppermint stems or leaves and synthesized chemically by adding water to the ketones or double bond compounds such as menthone, fragone, piperitone, thymol and isofragone.
The effects of menthol are well known in the modern medicine as well oriental medicine. L-menthol reduces the irritation of skin due to the effect of local anesthesia, and its derivative is reported to have an anti-inflammation effect. Further, it has an antibacterial effect.
Since the menthol has a lot of useful effects as seen above, it is used for toothpaste, jam, candy, tobacco, etc. However, it has not widely used in the field of cosmetics because it has strong fragrance and irritation on the eye. To overcome this problem, there were many studies to prepare menthol derivatives. For example, ester derivative of menthol has the effects of reducing the strong fragrance and irritation on the eye, but on the other hand, its useful effects also reduced.
Under this condition, the inventors of the present invention tried and studied to develop menthol derivatives to overcome the above problems. As the result, a menthol derivative obtained from phospho-diester of menthol and 3-amino propylphosphoric acid, a component used for anti-aging cosmetic composition, was found to reduce the irritation of menthol while maintaining the useful effects of menthol and found to show both the physiological effects of menthol itself and 3-aminopropylphosphoric acid when applied to living body.
The object of the present invention is to provide a menthol derivative with reduced irritation by comprising phosphorous group therein.
Further, another object of the present invention is to provide a method for preparing menthol derivative comprising phosphorous group.
To accomplish the above objects, the present invention provides a menthol derivative represented by the following Formula 1.
The above menthol derivative has reduced irritation compared with menthol itself, but has all the physiological effects of the menthol.
Further, the above menthol derivative is easily decomposed in the human body by the enzyme, and exhibits both the physiological activities of menthol and 3-aminopropylphosphoric acid.
Further, the present invention provides a method for preparing menthol derivative and its salt, by reacting menthol and phosphorous oxychloride in an organic solvent in the presence of organic base, further reacting with 3-amino propanol in the organic solvent in the presence of the organic base, then hydrolyzing and crystallizing the reaction resultant to obtain menthol derivative and the salt thereof.
More particularly, the method of the present invention comprises the steps of;
(A) reacting menthol and phosphorous oxychloride with an equivalence ratio of 1:1xcx9c1.3 in an organic solvent in the presence of organic base at 12xcx9c18xc2x0 C. for 1xcx9c2 hours to obtain dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one;
(B) reacting above obtained dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one with 3-amino propanol in the organic solvent in the presence of the organic base to obtain 2[5-methyl-2-(methylethyl)cyclohexyloxy]-1,3,2-oxazaphosphorine P-oxide;
(C) filtering the reaction resultant of step (B), and concentrating the filtrate under reduced pressure, then adding acid solution to the concentrated product and reacting at 5xcx9c100xc2x0 C. for 3xcx9c12 hours for hydrolysis; and
(D) crystallizing the product of step (C) with polar and organic solvent.
The present invention is described in detail hereinafter.
The method for preparing the menthol derivative of the present invention is schematized by the following Reaction Scheme 1. 
Each steps of the method for preparing the menthol derivative of the present invention is described hereinafter.
Step (A): reacting menthol and phosphorous oxychloride in an organic solvent in the presence of an organic base at 12xcx9c18xc2x0 C. for 1xcx9c2 hours to obtain dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one represented by structural formula (II) of the above Reaction Scheme 1.
In step (A), the equivalence ratio of menthol and phosphorous oxychloride is preferably 1:1xcx9c1.3. When the equivalence ratio is less than 1:1, the object material is not obtained; while, when the equivalence ratio is more than 1:1.3, an excessive amount of by-products are obtained. Therefore, when menthol and phosphorous oxychloride is reacted with the equivalence ratio of 1:1xcx9c1.3, the product, dichloro[5-methyl-2(mehtylethyl)cylclohexyloxy]phosphino-1-one in which menthol and phosphorous oxychloride is bonded with a ratio of 1:1 is obtained about 95%, and a by-product in which menthol and phosphorous oxychloride is bonded with a ratio of 2:1 is obtained less than 1xcx9c2%. Further, because that amount of by-product is removed by chromatography or by the separation method using the difference of solubility in toluene, the equivalence ratio of menthol and phosphorous oxychloride is preferably 1:1xcx9c1.3.
The reaction is preferably performed at 12xcx9c18xc2x0 C. for 1xcx9c2 hours, which can inhibit the production of by-product tha menthol and phosphorous oxychloride are bonded with a ratio of 2:1 or more; and especially, introducing ester group or amide group to protect a chlorine atom in the oxychloride is not needed, which makes the process simple.
The base used in step (A) comprises organic base such as pyridine and triethylamine; and triethylamine is preferable.
The organic solvent in step (A) comprises dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethylether, trichloro ethylene, benzene, toluene, etc.; and toluene is preferable.
The reaction temperature is preferably 12xcx9c18xc2x0 C. When the temperature is more than 18xc2x0 C., two or more equivalent amount of menthol is bonded to one equivalence of phosphorous oxychloride, which increase the by-product; while, when the reaction temperature is less than 12xc2x0 C., reaction rate decreases to make the reaction difficult and the yield decreases because non reacted components increases.
Step (B): reacting above obtained dichloro[5-methyl-2(mehtylethyl) cylclohexyloxy]phosphino-1-one and 3-aminopropanol in an organic solvent in the presence of an organic base.
The base used in step (B) comprises organic base such as pyridine and triethylamine that used in step (A), further, such bases as sodiumhydroxide and potassiumhydroxide may be used. Preferably, triethylamine is used.
The organic solvent in step (B) comprises inert solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform, ethylether, etc., and polar solvent such as methanol, ethanol, propanol, etc. Preferably, tetrahydrofuran is used.
Step (C): filtering the reaction resultant obtained in step (B) then concentrating the filtrate under reduced pressure, and adding acid solution to the residue (concentrated product above), and reacting at 5xcx9c100xc2x0 C. for 3xcx9c12 hours for hydrolysis.
The hydrolysis of the residue obtained by filtering the reaction resultant of step (B) and concentrating the filtrate under reduced pressure may be performed in general hydrolysis condition, that is, the hydrolysis may be performed by using acid catalysis such as strong acid cation (SAC) ion exchange resin, hydrochloric acid or sulfuric acid.
In detail, after adding acid solution to the compound obtained in step (B), the mixture is stirred while increasing the temperature up to 5xcx9c100xc2x0 C. to hydrolyze the Pxe2x80x94N bonding. Preferably, the hydrolysis can be performed proceeding the following steps of; filtering the reaction resultant of step (B) and concentrating the filtrate under reduced pressure to obtain a residue (concentrated product), then adding acid solution to the residue and reacting at 5xcx9c100xc2x0 C., preferably at 40xcx9c60xc2x0 C., for 3xcx9c12 hours, preferably for 8xcx9c12 hours. The acidity of the acid solvent is pH 1xcx9c5, preferably pH 2xcx9c4.
Step (D): crystallizing the above-obtained menthol 3-aminopropanol phospho-diester (menthol 3-aminopropylphosphate) by adding polar and organic solvent.
The solvent used in step (D) is not limited specifically, but preferably methanol, ethanol, isopropanol, acetone, tetrahydrofuran, acetonitrile or dioxane may be used.
The menthol derivative obtained above may be used as salt type after neutralization, for example, alkali metal salt type such as sodium salt, potassium salt, etc. is preferable usage type.
The menthol derivative and its salts of the present invention may be used for cosmetic composition and pharmaceutical composition. The amount of the menthol derivative or its salt for the cosmetic composition may be 0.001xcx9c30 wt. % to the weight of total composition. Further, in case that menthol derivative or its salt of the present invention is used for pharmaceutical composition, a person skilled in the art can determine the amount needed according to the state of the patient or the disease, and also can make preferable formulation thereof without difficulty.